This R03 proposal is in response to Research Objective #17, entitled Basic Underlying Mechanisms of Musculoskeletal Aging. Male osteoporosis and hip fractures, primarily diseases of older men, have been poorly studied until recently. While there are numerous factors that cause osteoporosis and determine fracture risk, decreases in gonadal steroids with aging are known to influence bone metabolism in both men and women. Recent evidence has demonstrated the importance of estrogen (E2) in male bone health. E2 exerts a variety of important physiological effects, which are mediated via two estrogen receptors found in adult bone, although the mechanisms by which they interact is not well understood. In preliminary work we have found that ovariectomy in mice is rapidly followed by an increase in the ability of bone marrow cells to differentiate into osteoclasts, the cells that mediate bone resorption. This finding suggests that E2 regulates the ability of hematopoietic precursor cells to differentiate into osteoclasts, a process that has not been adequately examined. The studies of this proposal represents a collaboration between basic and clinical researchers who wish to determine if human bone marrow cells from older men respond to E2 in a manner similar to that which we have demonstrated in our murine model. Since increased rates of bone resorption appear to be the earliest known effects of estrogen withdrawal on the human skeleton, a better understanding of this process may lead to more effective therapies for the treatment of osteoporosis in both men and women. A unique model in which to better understand the role of E2 in men is that of men undergoing hormonal suppression with LHRH agonists for locally advanced prostate cancer. This therapy leads to hypogonadism, with both low testosterone (T) and E2 levels within a few weeks. Since E2 therapy has been previously used to achieve medical castration, adding back E2 in these men is acceptable and allows the study of the mechanisms of E2 action on bone without the simultaneous influence of T. As the mechanisms of E2 action on male bone metabolism are better understood, it should be possible to analyze these interactions more precisely and develop more specific interventions based on a better understanding of these interactions.